Pharmaceutical compositions

ABSTRACT

Disclosed is a pharmaceutical composition suitable for oral administration in the form of a homogeneous solution which on exposure to water or gastrointestinal fluids forms an emulsion having a particle size of less than 5 microns, the solution containing:
         (a) a pharmaceutically effective amount of a cyclosporin, in particular Cyclosporin A,   (b) a carrier medium which is a dialkyl ester of an aliphatic or aromatic dioic acid, the alkyl group of said dialkyl ester having from 2 to 8 carbon atoms, and said aliphatic or aromatic dioic acid having from 6 to 20 carbon atoms,   (c) a co-carrier having a hydrophilic lipophilic balance (HLB) of from 3 to 6, and   (d) a non-ionic surfactant having a hydrophilic lipophilic balance (HLB) greater than 10.
 
Examples of the carrier medium are dibutyl sebacate and dibutyl phthalate. Examples of the co-carrier are glycerol monooleate, sorbitan monooleate, glycerol monocaprylate, and sorbitan monolaurate.

The present invention relates to pharmaceutical compositions, inparticular a micro-emulsion concentrate for cyclosporins.

The cyclosporins are a class of cyclic undecapeptides, with importantpharmacological activities, in particular immunosuppressive,anti-inflammatory and/or anti-parasitic activities. The first of thecyclosporins to be isolated, and the most commonly known cyclosporin, isCyclosporin A, formulations of which are commercially available underthe trade marks SANDIMMUNE and NEORAL

The cyclosporins are very lipophilic and hydrophobic compounds, whichare sparingly soluble in water, but dissolve readily in organic solventssuch as methanol, ethanol, chloroform and the like. The low solubilityin water results in extremely low bioavailability of the cyclosporinswhen administered orally. This may lead to higher dosages beingrequired, with the consequent possibility of undesirable side effects.Therefore, to provide an effective therapeutic concentration of the drugin the body when administered orally represents a considerablechallenge. Extensive research has been conducted to find cyclosporinformulations that are effective for oral administration. There are anumber of preparations of cyclosporins suitable for oral administrationproposed by the prior art.

Prior art formulations of cyclosporins for oral administration haveoften involved combinations of the cyclosporin with a surfactant, anoil, and a co-surfactant. Such formulations have been intended to bediluted with water prior to drinking. However, this is ratherinconvenient, and also the resulting aqueous composition has anunpleasant taste.

In order to alleviate the problems of having to dilute the compositionwith water prior to oral administration, and the unpleasant taste of theresulting solution, liquid compositions have been formulated into softcapsule preparations. For example, the formulation commerciallyavailable under the trade mark SANDIMMUNE is encapsulated in a softcapsule with a gelatine shell. The formulation contains ethanol in orderto solubilise the cyclosporin. However, the ethanol can permeate thegelatine shell of the capsule and is volatile at room temperature. Thismeans that the composition of the contents can vary during storage. Iftoo much ethanol is lost, the cyclosporin may precipitate from thecomposition, with adverse effects on the bioavailability. This resultsin uncertainties about dosage.

U.S. Pat. No. 4,388,307 discloses compositions comprising a cyclosporintogether with at least one of the following components:

-   -   a) a trans-esterification product of a natural or hydrogenated        vegetable oil triglyceride and a polyalkylene polyol;    -   b) a saturated fatty acid triglyceride; and    -   c) a mono- or di-glyceride.        It is preferred that ethanol be used as a further solubilising        agent, and the compositions for oral administration disclosed in        the Examples all contain ethanol.

U.S. Pat. No. 5,342,625 discloses pharmaceutical compositions comprisingcyclosporins in micro-emulsion pre-concentrate and micro-emulsion form.The compositions contain a cyclosporin disposed in a compositioncomprising a hydrophilic phase, a lipophilic phase and a surfactant. Thehydrophilic phase comprises 1,2-propylene glycol or R₁—(O—(CH₂))_(x)—OR₂wherein R₁ is a C₁₋₅ alkyl or a tetrahydrofurfuryl group, R₂ is a C₁₋₅alkyl or a tetrahydrofurfuryl group or is hydrogen, and X is from 1 to6. The lipophilic phase typically comprises a fatty acid triglyceride.The compositions may contain a C₁₋₅ alkanol, such as ethanol, as aco-solvent. However, the compositions disclosed in U.S. Pat. No.5,342,625 include components which are restricted for pharmaceutical useby several regulatory agencies world-wide, including the FDA, becausethey are not considered “Generally Recognised As Safe” (GRAS) for oraluse.

U.S. Pat. No. 5,759,997 discloses pharmaceutical compositions comprisinga cyclosporin, a fatty acid triglyceride, and a glycerol fatty acidpartial ester or propylene glycol or sorbitol complete or partial ester.The compositions may also comprise a viscosity reducer, such as thetrans-esterification product of a natural vegetable oil triglyceride anda polyalkylene polyol. Ethanol can also be used, but is less preferred.The compositions may also comprise an emulsifying agent, preferably atenside having a hydrophilic-lipophilic balance (HLB) of at least 10.

U.S. Pat. No. 6,057,289 discloses pharmaceutical compositions comprisingcyclosporin and a carrier comprising

-   -   (a) a cyclosporin solubilising agent consisting essentially of        C₆ to C₂₂ fatty acids; and    -   (b) a water-soluble non-ionic surfactant.        The surfactant should have a hydrophilic-lipophilic balance        (HLB) greater than 10, and suitable surfactants include        polyoxyethylene products of hydrogenated vegetable oils,        polyethoxylated castor oils or polyethoxylated hydrogenated        castor oil, polyoxyethylene-sorbitan-fatty acid esters,        polyoxyethylene castor oil derivatives and the like. The        compositions are for forming microemulsions upon contact with an        aqueous medium.

U.S. Pat. No. 5,858,401 discloses compositions that comprise acyclosporin, a medium chain monoglyceride of C₆ to C₁₂ fatty acids,having a monoglyceride content of at least 50%, and at least onesurfactant. The surfactant may be, for example, polyglycolisedglycerides or ethoxylated glycerides having a molecular weight of PEGbetween 400 and 2000 and a fatty acid chain length between C₆ to C₁₈.The compositions are for forming microemulsions upon contact with anaqueous medium.

Having regard to the state of the art, it is clear that it is desirableto provide further formulations of cyclosporins suitable for oraladministration, and in particular ones which can be formulated incapsules such as soft gelatine capsules, and which are emulsionconcentrates (that is, homogeneous solutions which on exposure to wateror gastrointestinal fluids form an emulsion having a particle size ofless than 5 microns), and preferably microemulsion concentrates, whichavoid the use of volatile components such as ethanol, and which utilisecompounds which are Generally Recognised As Safe (GRAS).

There is also a continued need to provide cyclosporin formulations fororal administration which can have high cyclosporin concentrations(thereby reducing the size of capsule required for a given dosage),which exhibit high oral bioavailability, and which are stable (inparticular stable against precipitation of the cyclosporin) uponstorage. It is also desirable that formulations should have as fewcomponents as possible, thereby resulting in ease of manufacture.

The present invention aims to provide cyclosporin compositions which, atleast to some extent, satisfy these requirements.

According to the present invention, there is provided a pharmaceuticalcomposition suitable for oral administration in the form of ahomogeneous solution which on exposure to water or gastrointestinalfluids forms an emulsion having a particle size of less than 5 microns,the solution comprising:

-   -   (a) a pharmaceutically effective amount of a cyclosporin,    -   (b) a carrier medium comprising a dialkyl ester of an aliphatic        or aromatic dioic acid, the alkyl group of said dialkyl ester        having from 2 to 8 carbon atoms, and said aliphatic or aromatic        dioic acid having from 6 to 20 carbon atoms,    -   (c) a co-carrier having a hydrophilic lipophilic balance (HLB)        of from 3 to 6, and    -   (d) a non-ionic surfactant having a hydrophilic lipophilic        balance (HLB) greater than 10.

The present invention is partly based upon the discovery that thecarrier medium as defined in (b) above represents a particularly goodsolvent medium for cyclosporins, and therefore it is possible to avoidco-solvents such as ethanol, propylene glycol, or the like. Thecompositions according to the present invention accordingly preferablydo not have such co-solvents, and in particular preferably do notcontain ethanol.

The compositions according to the present invention preferably do notcontain appreciable amounts of water, that is, they are substantiallywater-free.

The compositions according to the present invention exhibit excellentstability upon storage, and high concentrations of cyclosporins in thecompositions can be achieved.

The compositions according to the present invention are homogeneousmixtures which exhibit excellent bioavailability of the cyclosporin invivo.

The cyclosporin is preferably Cyclosporin A. The cyclosporin preferablymakes up from 1 to 25% by weight of the composition, more preferablymakes up from 5 to 20% by weight of the composition, and most preferablymakes up from 10 to 20% by weight of the composition. The cyclosporin ispresent in the composition of the present invention in pharmaceuticallyeffective amounts. These amounts are well-known in the art. For example,when treating chronic inflammations or provoking an immunosuppressiveeffect, it is preferred that the daily dose ranges from about 3 mg/kg toabout 50 mg/kg.

The carrier medium may comprise a dialkyl ester of an aliphatic or of anaromatic acid. When the acid is an aliphatic acid, the acid preferablyhas from 8 to 12 carbon atoms, and more preferably has 10 carbon atoms.Most preferably, the aliphatic acid is sebacic acid. When the acid is anaromatic acid, the acid preferably has from 6 to 10 carbon atoms, andmore preferably has 8 carbon atoms. Most preferably, the aromatic acidis phthalic acid. Each alkyl group of the dialkyl ester (which may bethe same or different, but is preferably the same) has from 2 to 8carbon atoms, preferably has from 3 to 6 carbon atoms, more preferablyhas 4 carbon atoms, and most preferably is an n-butyl group.

Thus, the most preferred compounds for the carrier medium are dibutylphthalate and dibutyl sebacate.

The carrier medium may comprise mixtures of compounds as defined herein.

The carrier medium preferably makes up from 20 to 60% by weight of thecomposition, more preferably makes up from 25 to 50% by weight of thecomposition, and most preferably makes up from 30 to 40% by weight ofthe composition.

The non-ionic surfactant preferably makes up from 5 to 40% by weight ofthe composition, more preferably makes up from 10 to 35% by weight ofthe composition, and most preferably makes up from 15 to 25% by weightof the composition.

The Hydrophilic Lipophilic Balance (HLB) of the non-ionic surfactant isgreater than 10, more preferably greater than 12 and most preferablygreater than 14.

The non-ionic surfactant must be capable of forming a stable emulsion,preferably a fine emulsion (particle size less than 1 micron), and morepreferably a microemulsion, of the composition when it is brought intocontact with aqueous fluid, such as in the G.I. tract.

The non-ionic surfactant is preferably selected from the groupconsisting of: polyoxyethylene products of hydrogenated vegetable oils,polyethoxylated castor oils, polyethoxylated hydrogenated castor oil,polyoxyethylene-sorbitan-fatty acid esters, and polyoxyethylene castoroil derivatives. Particularly preferred surfactants are set out inTable 1. Mixtures of these surfactants can also be used.

TABLE 1 Trade Name Description TWEEN 20 Polyoxyethylene (20) sorbitanmonolaurate TWEEN 40 Polyoxyethylene (20) sorbitan monopalmitate TWEEN60 Polyoxyethylene (20) sorbitan monostearate TWEEN 80 Polyoxyethylene(20) sorbitan monooleate NIKKOL HCO30 PEG-30 hydrogenated castor oilNIKKOL HCO40 PEG-40 hydrogenated castor oil NIKKOL HCO50 PEG-50hydrogenated castor oil NIKKOL HCO60 PEG-60 hydrogenated castor oilCREMOPHORE RH40 Polyoxyethylene 40 castor oil CREMOPHORE RH60Polyoxyethylene 60 castor oil CREMOPHORE EL35 Polyoxyethylene 35 castoroil

The co-carrier is added to form an isotropic mixture. The co-carrierpreferably makes up from 25 to 50% by weight of the composition, andmore preferably from 30 to 40% by weight of the composition.

The co-carrier has an HLB value of from 3 to 6, and any such co-carrierthat is safe for oral administration is suitable. The co-carrier ispreferably a monoester of glycerol or sorbitan with an aliphaticmonocarboxylic acid having from 6 to 30 carbon atoms. Preferably, thealiphatic monocarboxylic acid has from 8 to 18 carbon atoms.Particularly preferred co-carriers are glycerol monooleate, glycerolmonocaprylate, sorbitan monooleate, and sorbitan monolaurate, andmixtures thereof Such suitable co-carriers are commercially available.

The pharmaceutical compositions according to the present invention mayfurther comprise an antioxidant. This antioxidant, when present, ispreferably present in an amount of from 0.01% to 2% by weight of thecomposition, and more preferably from 0.5 to 1% by weight of thecomposition. The antioxidant may be any suitable antioxidant, such asare well known to those skilled in the art. Particularly preferredantioxidants are butyl hydroxy anisole (BHA), butyl hydroxy toluene(BHT), and alpha-tocopherol.

Other additives, excipients, and diluents normally used in thepharmaceutical arts may optionally be added to the composition. Theseinclude thickening agents, dispersing agents, flavouring agents,sweetening agents, colouring agents, stabilising agents (including pHstabilisers), and preservatives. However, the compositions of thepresent invention preferably consist only of the components defined inclaim 1, or at least comprise at least 90%, more preferably at least95%, and more preferably at least 98% by weight of the componentsdefined in claim 1.

The pharmaceutical compositions according to the present invention maybe formulated as a drinking solution, or as a hard or soft capsule. Softcapsule formulations are particularly preferred. Gelatine capsules arealso preferred.

The pharmaceutical compositions according to the present invention canbe conveniently prepared by uniformly and thoroughly mixing the carriermedium, the cyclosporin, and the surfactant together at room temperatureor at slightly elevated temperature, such as a temperature up to 40° C.,until a clear solution is obtained, and then cooling the composition toroom temperature. The other additives indicated above are thenthoroughly admixed therewith. The cyclosporin remains in solution anddoes not crystallise or precipitate out.

Compositions according to the present invention are preferably foradministration to mammals, and especially to humans. It is preferredthat the pharmaceutical compositions of the present invention areadministered in capsule, liquid-oral, drink solution, or the like form.In a preferred embodiment, the composition is in a form adapted for oraladministration in oral unit dosage form. Capsules, e.g., soft or hardgelatine capsules, which represent the preferred oral dosage form, arespecially suitable unit dosage forms for oral administration.

Oral unit dosage forms in accordance with the present invention willsuitably comprise from 5 to 400 mg and more preferably from 20 to 200mg, e.g., 25, 50, 100, 125, 150, or 200 mg of cyclosporin. The dosage ofthe drug and the number of times administered to the patient will varydepending on several factors such as: the age of the patient, theseverity of the condition of the patient, and past medical history, andwill be a matter to be determined by the attending physician.

When the composition of the present invention is prepared in the form ofa soft or hard capsule, the composition may be encapsulated in agelatine shell which contains any conventional plasticizer. Suitableplasticizers are: glycerine, sorbitol, hexanetriol propylene carbonate,hexane glycol, sorbitans, tetrahydrofuryl alcohol ether, diethyleneglycol monoethyl ether, 1,3-trimethyl-2-imidazolidone,dimethylisosorbide, and mixtures of these. However, the plasticizer isnot limited to those just mentioned, and any suitable plasticizer can beused.

Encapsulation can be achieved by standard techniques which are wellknown in the art.

Compositions according to the present invention exhibit high solubilityof cyclosporin, thereby reducing the size of the capsule or other oralunit dosage form. They also employ only materials that are GRAS for oraluse.

The invention will now be further described with reference to thefollowing Examples, it being understood that these are intended toillustrate the invention, and in no way to limit its scope.

EXAMPLES

The examples used the ingredients and in the amounts indicated in Table2. Cyclosporin A was dissolved in the carrier medium, the othercomponents were added, and the mixture was mixed for from 10 to 30minutes at room temperature until the solution was homogeneous.

The solution was then stored overnight up to 24 hours to ensure that nocrystallisation occurred.

To verify that an emulsion was formed, one part of each composition wasadded to 10 parts of water and stirred gently. There was formed a fineemulsion having a particle size of less than 5 microns, and theCyclosporin A did not precipitate or crystallise out.

The compositions are suitable for encapsulation into a hard or softgelatine capsule.

TABLE 2 Example 1 Example 2 Example 3 Ingredients weight/mg weight/mgweight/mg Cyclosporin A 100 100 100 Dibutyl sebacate 220 220 220Glycerol mono oleate 220 Glycerol mono caprylate 220 Sorbitan monooleate 220 Polyoxyethylene 35 castor 150 150 150 oil (cremophore EL)Alpha tocopherol 5 5 5 TOTAL 695 mg 695 mg 695 mg

Thus, it can be seen that the compositions of the present inventionallow high concentrations of cyclosporins to be obtained, which exhibitgood stability on storage. The compositions of the present inventionallow higher concentrations of cyclosporin to be obtained than currentcommercial preparations (Sandimune, Neoral).

1. A pharmaceutical composition suitable for oral administration in theform of a homogeneous solution which on exposure to water orgastrointestinal fluids forms an emulsion having a particle size of lessthan 5 microns, the solution comprising: (a) a pharmaceuticallyeffective amount of a cyclosporin, (b) a carrier medium comprising adialkyl ester of an aliphatic or aromatic dioic acid, the alkyl group ofsaid dialkyl ester having from 2 to 8 carbon atoms, and said aliphaticor aromatic dioic acid having from 6 to 20 carbon atoms, (c) aco-carrier having a hydrophilic lipophilic balance (HLB) of from 3 to 6,and (d) a non-ionic surfactant having a hydrophilic lipophilic balance(HLB) greater than
 10. 2. A pharmaceutical composition according toclaim 1 wherein the carrier medium comprises a di-C₃₋₆-alkyl ester of aC₈₋₁₂-aliphatic dioic acid or C₆₋₁₀-aromatic dioic acid.
 3. Apharmaceutical composition according to claim 1 wherein the carriermedium comprises a di-C₄-alkyl ester of a C₁₀-aliphatic dioic acid orC8-aromatic dioic acid.
 4. A pharmaceutical composition according toclaim 1 wherein the carrier medium comprises a dibutyl ester of analiphatic or aromatic dioic acid.
 5. A pharmaceutical compositionaccording to claim 4, wherein the carrier medium comprises dibutylsebacate or dibutyl phthalate.
 6. A pharmaceutical composition accordingto claim 1, wherein the cyclosporin is 1 to 25% by weight of thecomposition, the carrier medium is 20 to 60% by weight of thecomposition, the non-ionic surfactant is 15 to 25% by weight of thecomposition, and the co-carrier is 25 to 50% by weight of thecomposition.
 7. A pharmaceutical composition according to claim 6,wherein the cyclosporin is 5 to 20% by weight of the composition, thecarrier medium is 25 to 50% by weight of the composition, and thenon-ionic surfactant is 10 to 35% by weight of the composition.
 8. Apharmaceutical composition according to claim 7, wherein the cyclosporinis 10 to 20% by weight of the composition, the carrier medium is 30 to40% by weight of the composition, the non-ionic surfactant is 15 to 25%by weight of the composition, and the co-carrier is 30 to 40% by weightof the composition.
 9. A pharmaceutical composition according to claim1, wherein the non-ionic surfactant is selected from the groupconsisting of: polyoxyethylated hydrogenated vegetable oil,polyethoxylated castor oil, polyethoxylated hydrogenated castor oil,polyoxyethylene-sorbitan-fatty acid ester, polyoxyethylene castor oilderivative, and mixtures thereof.
 10. A pharmaceutical compositionaccording to claim 9, wherein the non-ionic surfactant is selected fromthe group consisting of polyoxyethylene (20) sorbitan monolaurate,polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20)sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, PEG-30hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-50hydrogenated castor oil, PEG-60 hydrogenated castor oil, polyoxyethylene(40) castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (35)castor oil, and mixtures thereof.
 11. A pharmaceutical compositionaccording to claim 1, wherein the co-carrier is selected from the groupconsisting of monoesters of glycerol or sorbitan with an aliphaticmonocarboxylic acid having from 6 to 30 carbon atoms, preferably from 8to 18 carbon atoms, and mixtures thereof.
 12. A pharmaceuticalcomposition according to claim 11, wherein the co-carrier is selectedfrom the group consisting of monoesters of glycerol or sorbitan with analiphatic monocarboxylic acid having from 8 to 18 carbon atoms andmixtures thereof.
 13. A pharmaceutical composition according to claim12, wherein the co-carrier is selected from the group consisting ofglycerol monooleate, sorbitan monooleate, glycerol monocaprylate,sorbitan monolaurate, and mixtures thereof.
 14. A pharmaceuticalcomposition according to claim 1, further comprising an antioxidant. 15.A pharmaceutical composition according to claim 14, wherein theantioxidant is present in an amount of from 0.01% to 2% by weight of thetotal composition.
 16. A pharmaceutical composition according to claim14, wherein the antioxidant is selected from the group consisting ofBHA, BHT, and alpha-tocopherol.
 17. A pharmaceutical compositionaccording to claim 1, wherein the cyclosporin is Cyclosporin A.
 18. Apharmaceutical composition according to claim 1, wherein the cyclosporinis 1 to 25% by weight of the composition, the carrier medium is 20 to60% by weight of the composition and comprises a di-C₃₋₆-alkyl ester ofa C₈₋₁₂-aliphatic dioic acid or C₆₋₁₀-aromatic dioic acid, the non-ionicsurfactant is 15 to 25% by weight of the composition and has an HLBgreater than 10, the co-carrier is 25 to 50% by weight of thecomposition, and the composition contains from 0.01% to 2 % by weight ofan antioxidant.
 19. A pharmaceutical composition according to claim 18,wherein the cyclosporin is 10 to 20% by weight of the composition andcomprises Cyclosporin A, the carrier medium is 30 to 40% by weight ofthe composition and comprises dibutyl sebacate or dibutyl phthalate, thenon-ionic surfactant is 15 to 25% by weight of the composition and has aHLB greater than 14, the co-carrier is 30 to 40% by weight of thecomposition and the composition contains from 0.5% to 21% by weight ofan antioxidant selected from the group consisting of BHA, BHT, andalpha-tocopherol.
 20. A pharmaceutical composition according to claim 1,formulated as a drinking solution.
 21. A pharmaceutical compositionaccording to claim 1 formulated as a hard or soft capsule.
 22. Apharmaceutical composition according to claim 19 contained within a softgelatine capsule.